Investigational New Drugs

, Volume 22, Issue 4, pp 427–435

Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs

  • Susan M. Chang
  • John Kuhn
  • Patrick Wen
  • Harry Greenberg
  • David Schiff
  • Charles Conrad
  • Karen Fink
  • H. Ian Robins
  • Timothy Cloughesy
  • Lisa De Angelis
  • Jeffrey Razier
  • Kenneth Hess
  • Janet Dancey
  • Michael D. Prados
Article

DOI: 10.1023/B:DRUG.0000036685.72140.03

Cite this article as:
Chang, S.M., Kuhn, J., Wen, P. et al. Invest New Drugs (2004) 22: 427. doi:10.1023/B:DRUG.0000036685.72140.03

Abstract

Objectives: CCI-779 is an ester of the immunosuppressive agent sirolimus (rapamycin) that causes cell-cycle arrest at G1 via inhibition of key signaling pathways resulting in inhibition of RNA translation. Antitumor activity has been demonstrated using cell lines and animal models of malignant glioma. Patients receiving enzyme-inducing anti-epileptic drugs (EIAEDs) can have altered metabolism of drugs like CCI-779 that are metabolized through the hepatic cytochrome P450 enzyme system. The objectives of this study were to determine the pharmacokinetic profile and the maximum tolerated dose of CCI-779 in patients with recurrent malignant gliioma taking EIAEDs. Study design: The starting dose of CCI-779 was 250 mg intravenously (IV) administered weekly on a continuous basis. Standard dose escalation was performed until the maximum tolerated dose was established. Toxicity was assessed using the National Cancer Institute common toxicity criteria. Results: Two of 6 patients treated at the second dose level of 330 mg sustained a dose-limiting toxicity: grade III stomatitis, grade 3 hypercholesterolemia, or grade 4 hypertriglyceridemia. The maximum tolerated dose was reached at 250 mg IV. Pharmacokinetic profiles were similar to those previously described, but the area under the whole blood concentration-time curve of rapamycin was 1.6 fold lower for patients on EIAEDs. Conclusions: The recommended phase II dose of CCI 779 for patients on enzyme-inducing antiepileptic drugs is 250 mg IV weekly. A phase II study is ongoing to determine the efficacy of this agent.

chemotherapyrapamycinCCI-779toxicity

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Susan M. Chang
    • 1
  • John Kuhn
    • 2
  • Patrick Wen
    • 3
  • Harry Greenberg
    • 4
  • David Schiff
    • 5
  • Charles Conrad
    • 6
  • Karen Fink
    • 7
  • H. Ian Robins
    • 8
  • Timothy Cloughesy
    • 9
  • Lisa De Angelis
    • 10
  • Jeffrey Razier
    • 10
  • Kenneth Hess
    • 6
  • Janet Dancey
    • 11
  • Michael D. Prados
    • 1
  1. 1.University of CaliforniaSan Francisco
  2. 2.University of TexasSan Antonio
  3. 3.Dana Farber Cancer InstituteUSA
  4. 4.University of MichiganUSA
  5. 5.University of VirginiaUSA
  6. 6.MD Anderson Cancer CenterUSA
  7. 7.University of TexasSouthwestern
  8. 8.Unversity of WisconsinUSA
  9. 9.University of CaliforniaLos Angeles
  10. 10.Memorial Sloan Kettering Cancer CenterUSA
  11. 11.Cancer Therapy Evaluation ProgramNational Cancer InstituteUSA